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Holling T, Abdelrazek IM, Elhady GM, Abd Elmaksoud M, Ryu SW, Abdalla E, Kutsche K. A homozygous nonsense variant in the alternatively spliced VLDLR exon 4 causes a neurodevelopmental disorder without features of VLDLR cerebellar hypoplasia. J Hum Genet 2024; 69:623-628. [PMID: 39085459 PMCID: PMC11599036 DOI: 10.1038/s10038-024-01279-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 07/17/2024] [Accepted: 07/20/2024] [Indexed: 08/02/2024]
Abstract
VLDLR cerebellar hypoplasia is characterized by intellectual disability, non-progressive cerebellar ataxia, and seizures. The characteristic MRI findings include hypoplasia of the inferior portion of the cerebellar vermis and hemispheres, simplified cortical gyration, and a small brain stem. Biallelic VLDLR pathogenic variants cause loss-of-function of the encoded very low-density lipoprotein receptor. VLDLR exons 4 and 16 are alternatively spliced, resulting in the expression of four transcript variants, including two exon 4-lacking mRNAs expressed in the human brain. Previously reported VLDLR pathogenic variants affect all four transcript variants. Here we report on two sisters with facial dysmorphism, microcephaly, intellectual disability, and normal brain imaging. Exome sequencing in one patient identified the homozygous VLDLR nonsense variant c.376C>T; p.(Gln126*) in exon 4; her similarly affected sister also carried the homozygous variant and parents were heterozygous carriers. VLDLR transcript analysis identified mRNAs with and without exon 4 in patient fibroblasts, while exon 4-containing VLDLR mRNAs were predominantly detected in control fibroblasts. We found significantly reduced VLDLR mRNA levels in patient compared to control cells, likely caused by nonsense-mediated mRNA decay of exon 4-containing VLDLR transcripts. Expression of neuronal VLDLR isoforms produced from exon 4-lacking transcripts may have protected both patients from developing the cerebellar hypoplasia phenotype.
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Affiliation(s)
- Tess Holling
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ibrahim M Abdelrazek
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Ghada M Elhady
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Marwa Abd Elmaksoud
- Neurology Unit, Pediatric Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | | | - Ebtesam Abdalla
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Kerstin Kutsche
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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Huang JK, Lee HC. Emerging Evidence of Pathological Roles of Very-Low-Density Lipoprotein (VLDL). Int J Mol Sci 2022; 23:4300. [PMID: 35457118 PMCID: PMC9031540 DOI: 10.3390/ijms23084300] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 04/10/2022] [Accepted: 04/11/2022] [Indexed: 12/18/2022] Open
Abstract
Embraced with apolipoproteins (Apo) B and Apo E, triglyceride-enriched very-low-density lipoprotein (VLDL) is secreted by the liver into circulation, mainly during post-meal hours. Here, we present a brief review of the physiological role of VLDL and a systemic review of the emerging evidence supporting its pathological roles. VLDL promotes atherosclerosis in metabolic syndrome (MetS). VLDL isolated from subjects with MetS exhibits cytotoxicity to atrial myocytes, induces atrial myopathy, and promotes vulnerability to atrial fibrillation. VLDL levels are affected by a number of endocrinological disorders and can be increased by therapeutic supplementation with cortisol, growth hormone, progesterone, and estrogen. VLDL promotes aldosterone secretion, which contributes to hypertension. VLDL induces neuroinflammation, leading to cognitive dysfunction. VLDL levels are also correlated with chronic kidney disease, autoimmune disorders, and some dermatological diseases. The extra-hepatic secretion of VLDL derived from intestinal dysbiosis is suggested to be harmful. Emerging evidence suggests disturbed VLDL metabolism in sleep disorders and in cancer development and progression. In addition to VLDL, the VLDL receptor (VLDLR) may affect both VLDL metabolism and carcinogenesis. Overall, emerging evidence supports the pathological roles of VLDL in multi-organ diseases. To better understand the fundamental mechanisms of how VLDL promotes disease development, elucidation of the quality control of VLDL and of the regulation and signaling of VLDLR should be indispensable. With this, successful VLDL-targeted therapies can be discovered in the future.
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Affiliation(s)
- Jih-Kai Huang
- Department of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Hsiang-Chun Lee
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Lipid Science and Aging Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80708, Taiwan
- Graduate Institute of Animal Vaccine Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
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Yao F, Zhang K, Zhang Y, Guo Y, Li A, Xiao S, Liu Q, Shen L, Ni J. Identification of Blood Biomarkers for Alzheimer's Disease Through Computational Prediction and Experimental Validation. Front Neurol 2019; 9:1158. [PMID: 30671019 PMCID: PMC6331438 DOI: 10.3389/fneur.2018.01158] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 12/14/2018] [Indexed: 12/15/2022] Open
Abstract
Background: Alzheimer's disease (AD) is the major cause of dementia in population aged over 65 years, accounting up to 70% dementia cases. However, validated peripheral biomarkers for AD diagnosis are not available up to present. In this study, we adopted a new strategy of combination of computational prediction and experimental validation to identify blood protein biomarkers for AD. Methods: First, we collected tissue-based gene expression data of AD patients and healthy controls from GEO database. Second, we analyzed these data and identified differentially expressed genes for AD. Third, we applied a blood-secretory protein prediction program on these genes and predicted AD-related proteins in blood. Finally, we collected blood samples of AD patients and healthy controls to validate the potential AD biomarkers by using ELISA experiments and Western blot analyses. Results: A total of 2754 genes were identified to express differentially in brain tissues of AD, among which 296 genes were predicted to encode AD-related blood-secretory proteins. After careful analysis and literature survey on these predicted blood-secretory proteins, ten proteins were considered as potential AD biomarkers, five of which were experimentally verified with significant change in blood samples of AD vs. controls by ELISA, including GSN, BDNF, TIMP1, VLDLR, and APLP2. ROC analyses showed that VLDLR and TIMP1 had excellent performance in distinguishing AD patients from controls (area under the curve, AUC = 0.932 and 0.903, respectively). Further validation of VLDLR and TIMP1 by Western blot analyses has confirmed the results obtained in ELISA experiments. Conclusion: VLDLR and TIMP1 had better discriminative abilities between ADs and controls, and might serve as potential blood biomarkers for AD. To our knowledge, this is the first time to identify blood protein biomarkers for AD through combination of computational prediction and experimental validation. In addition, VLDLR was first reported here as potential blood protein biomarker for AD. Thus, our findings might provide important information for AD diagnosis and therapies.
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Affiliation(s)
- Fang Yao
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Science and Oceanography, Shenzhen University, Shenzhen, China.,Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, China
| | - Kaoyuan Zhang
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Yan Zhang
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Yi Guo
- Department of Neurology, Shenzhen People's Hospital, Shenzhen, China
| | - Aidong Li
- Department of Rehabilitation, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Shifeng Xiao
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Qiong Liu
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Liming Shen
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
| | - Jiazuan Ni
- Shenzhen Key Laboratory of Marine Biotechnology and Ecology, College of Life Science and Oceanography, Shenzhen University, Shenzhen, China
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Dlugosz P, Nimpf J. The Reelin Receptors Apolipoprotein E receptor 2 (ApoER2) and VLDL Receptor. Int J Mol Sci 2018; 19:E3090. [PMID: 30304853 PMCID: PMC6213145 DOI: 10.3390/ijms19103090] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/03/2018] [Accepted: 10/03/2018] [Indexed: 01/28/2023] Open
Abstract
Apolipoprotein E receptor 2 (ApoER2) and VLDL receptor belong to the low density lipoprotein receptor family and bind apolipoprotein E. These receptors interact with the clathrin machinery to mediate endocytosis of macromolecules but also interact with other adapter proteins to perform as signal transduction receptors. The best characterized signaling pathway in which ApoER2 and VLDL receptor (VLDLR) are involved is the Reelin pathway. This pathway plays a pivotal role in the development of laminated structures of the brain and in synaptic plasticity of the adult brain. Since Reelin and apolipoprotein E, are ligands of ApoER2 and VLDLR, these receptors are of interest with respect to Alzheimer's disease. We will focus this review on the complex structure of ApoER2 and VLDLR and a recently characterized ligand, namely clusterin.
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Affiliation(s)
- Paula Dlugosz
- Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University Vienna, 1030 Vienna, Austria.
| | - Johannes Nimpf
- Department of Medical Biochemistry, Max F. Perutz Laboratories, Medical University Vienna, 1030 Vienna, Austria.
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Reddy SS, Connor TE, Weeber EJ, Rebeck W. Similarities and differences in structure, expression, and functions of VLDLR and ApoER2. Mol Neurodegener 2011; 6:30. [PMID: 21554715 PMCID: PMC3113299 DOI: 10.1186/1750-1326-6-30] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2011] [Accepted: 05/09/2011] [Indexed: 11/29/2022] Open
Abstract
Very Low Density Lipoprotein Receptor (VLDLR) and Apolipoprotein E Receptor 2 (ApoER2) are important receptors in the brain for mediating the signaling effects of the extracellular matrix protein Reelin, affecting neuronal function in development and in the adult brain. VLDLR and ApoER2 are members of the low density lipoprotein family, which also mediates the effects of numerous other extracellular ligands, including apolipoprotein E. Although VLDLR and ApoER2 are highly homologous, they differ in a number of ways, including structural differences, expression patterns, alternative splicing, and binding of extracellular and intracellular proteins. This review aims to summarize important aspects of VLDLR and ApoER2 that may account for interesting recent findings that highlight the unique functions of each receptor.
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Affiliation(s)
- Sunil S Reddy
- Department of Neuroscience; Georgetown University Medical Center, 3970 Reservoir Rd, NW, Washington, DC, 20007, USA.
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He L, Lu Y, Wang P, Zhang J, Yin C, Qu S. Up-regulated expression of type II very low density lipoprotein receptor correlates with cancer metastasis and has a potential link to β-catenin in different cancers. BMC Cancer 2010; 10:601. [PMID: 21047397 PMCID: PMC2988033 DOI: 10.1186/1471-2407-10-601] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2010] [Accepted: 11/03/2010] [Indexed: 11/24/2022] Open
Abstract
Background Very low density lipoprotein receptor (VLDLR) has been considered as a multiple function receptor due to binding numerous ligands, causing endocytosis and regulating cellular signaling. Our group previously reported that enhanced activity of type II VLDLR (VLDLR II), one subtype of VLDLR, promotes adenocarcinoma SGC7901 cells proliferation and migration. The aim of this study is to explore the expression levels of VLDLR II in human gastric, breast and lung cancer tissues, and to investigate its relationship with clinical characteristics and β-catenin expression status. Methods VLDLR II expression was examined using immunohistochemistry (IHC) and Western blot in tumor tissues from 213 gastric, breast and lung cancer patients, tumor adjacent noncancerous tissues by same methods. Correlations between VLDLR II and clinical features, as well as β-catenin expression status were evaluated by statistical analysis. Results The immunohistochemical staining of VLDLR II showed statistical difference between tumor tissues and tumor adjacent noncancerous tissues in gastric, breast and lung cancers (P = 0.034, 0.018 and 0.043, respectively). Moreover, using Western, we found higher VLDLR II expression levels were associated with lymph node and distant metastasis in gastric and breast cancer (P < 0.05). Furthermore, highly significant positive correlations were found between VLDLR II and β-catenin in gastric cancer (r = 0.689; P < 0.001)breast cancer (r = 0.594; P < 0.001). Conclusions According to the results of the current study, high VLDLR II expression is correlated with lymph node and distant metastasis in gastric and breast cancer patients, the data suggest that VLDLR II may be a clinical marker in cancers, and has a potential link with β-catenin signaling pathway. This is the first to reveal the closer relationship of VLDLR II with clinical information.
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Affiliation(s)
- Lei He
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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Sakai K, Tiebel O, Ljungberg MC, Sullivan M, Lee HJ, Terashima T, Li R, Kobayashi K, Lu HC, Chan L, Oka K. A neuronal VLDLR variant lacking the third complement-type repeat exhibits high capacity binding of apoE containing lipoproteins. Brain Res 2009; 1276:11-21. [PMID: 19393635 PMCID: PMC2733343 DOI: 10.1016/j.brainres.2009.04.030] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2009] [Revised: 03/30/2009] [Accepted: 04/12/2009] [Indexed: 12/31/2022]
Abstract
Very-low-density lipoprotein receptor (VLDLR) is a multi ligand apolipoprotein E (apoE) receptor and is involved in brain development through Reelin signaling. Different forms of VLDLR can be generated by alternative splicing. VLDLR-I contains all exons. VLDLR-II lacks an O-linked sugar domain encoded by exon 16, while VLDLR-III lacks the third complement-type repeat in the ligand binding domain encoded by exon 4. We quantitatively compared lipoprotein binding to human VLDLR variants and analyzed their mRNA expression in both human cerebellum and mouse brain. VLDLR-III exhibited the highest capacity in binding to apoE enriched beta-VLDL in vitro and was more effective in removing apoE containing lipoproteins from the circulation than other variants in vivo. In human cerebellum, the major species was VLDLR-II, while the second most abundant species was a newly identified VLDLR-IV which lacks both exon 4 and 16. VLDLR-I was present at low levels. In adult mice, exon 4 skipping varied between 30 and 47% in different brain regions, while exon 16 skipping ranged by 51-76%. Significantly higher levels of VLDLR proteins were found in mouse cerebellum and cerebral cortex than other regions. The deletions of exon 4 and exon 16 frequently occurred in primary neurons, indicating that newly identified variant VLDLR-IV is abundant in neurons. In contrast, VLDLR mRNA lacking exon 4 was not detectable in primary astrocytes. Such cell type-specific splicing patterns were found in both mouse cerebellum and cerebral cortex. These results suggest that a VLDLR variant lacking the third complement-type repeat is generated by neuron-specific alternative splicing. Such differential splicing may result in different lipid uptake in neurons and astrocytes.
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Affiliation(s)
- Keiko Sakai
- Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Oliver Tiebel
- Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | | | - Merry Sullivan
- Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hye-Jeong Lee
- Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Tomoya Terashima
- Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Rongying Li
- Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kunihisa Kobayashi
- Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hui-Chen Lu
- Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Lawrence Chan
- Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kazuhiro Oka
- Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
- Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
- Medicine, Baylor College of Medicine, Houston, TX 77030, USA
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Yang P, Liu Z, Wang H, Tian J, Li Y, Zong Y, Qu S. Enhanced activity of very low density lipoprotein receptor II promotes SGC7901 cell proliferation and migration. Life Sci 2009; 84:402-8. [DOI: 10.1016/j.lfs.2008.12.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2008] [Revised: 11/26/2008] [Accepted: 12/21/2008] [Indexed: 10/21/2022]
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Prinzen C, Trümbach D, Wurst W, Endres K, Postina R, Fahrenholz F. Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice. BMC Genomics 2009; 10:66. [PMID: 19196476 PMCID: PMC2647556 DOI: 10.1186/1471-2164-10-66] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2008] [Accepted: 02/05/2009] [Indexed: 01/03/2023] Open
Abstract
Background In a transgenic mouse model of Alzheimer disease (AD), cleavage of the amyloid precursor protein (APP) by the α-secretase ADAM10 prevented amyloid plaque formation, and alleviated cognitive deficits. Furthermore, ADAM10 overexpression increased the cortical synaptogenesis. These results suggest that upregulation of ADAM10 in the brain has beneficial effects on AD pathology. Results To assess the influence of ADAM10 on the gene expression profile in the brain, we performed a microarray analysis using RNA isolated from brains of five months old mice overexpressing either the α-secretase ADAM10, or a dominant-negative mutant (dn) of this enzyme. As compared to non-transgenic wild-type mice, in ADAM10 transgenic mice 355 genes, and in dnADAM10 mice 143 genes were found to be differentially expressed. A higher number of genes was differentially regulated in double-transgenic mouse strains additionally expressing the human APP[V717I] mutant. Overexpression of proteolytically active ADAM10 affected several physiological pathways, such as cell communication, nervous system development, neuron projection as well as synaptic transmission. Although ADAM10 has been implicated in Notch and β-catenin signaling, no significant changes in the respective target genes were observed in adult ADAM10 transgenic mice. Real-time RT-PCR confirmed a downregulation of genes coding for the inflammation-associated proteins S100a8 and S100a9 induced by moderate ADAM10 overexpression. Overexpression of the dominant-negative form dnADAM10 led to a significant increase in the expression of the fatty acid-binding protein Fabp7, which also has been found in higher amounts in brains of Down syndrome patients. Conclusion In general, there was only a moderate alteration of gene expression in ADAM10 overexpressing mice. Genes coding for pro-inflammatory or pro-apoptotic proteins were not over-represented among differentially regulated genes. Even a decrease of inflammation markers was observed. These results are further supportive for the strategy to treat AD by increasing the α-secretase activity.
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Affiliation(s)
- Claudia Prinzen
- Johannes Gutenberg-University, Institute of Biochemistry, Mainz, Mainz, Germany
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Chen T, Wu F, Chen FM, Tian J, Qu S. Variations of very low-density lipoprotein receptor subtype expression in gastrointestinal adenocarcinoma cells with various differentiations. World J Gastroenterol 2005; 11:2817-21. [PMID: 15884130 PMCID: PMC4305924 DOI: 10.3748/wjg.v11.i18.2817] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: This study is aimed at investigating the expression and possible significances of very low-density lipoprotein receptor (VLDLR) subtypes in gastroenteric adenocarcinoma tissues and cells with various differentiations.
METHODS: Thirty-one cases of gastroenteric carcinoma/adjacent normal tissues were enrolled in the study, which were diagnosed and classified by the clinicopathological diagnosis. The expression of VLDLR subtypes was detected in gastroenteric carcinoma/adjacent normal tissues and three various differentiated human gastric adenocarcinoma cell lines (MKN28, SGC7901 and MKN45) by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis.
RESULTS: Two VLDLR subtypes, namely, type II VLDLR and type I VLDLR, were found to express changes in gastroenteric carcinoma tissues, their adjacent normal tissue, and gastric adenocarcinoma cell lines as well. Type II VLDLR is predominantly expressed in poorly- or moderately-differentiated gastroenteric carcinoma tissues and gastric adenocarcinoma cell lines, whereas type I VLDLR is mainly detected in well-differentiated intestinal carcinoma tissues and gastric adenocarcinoma cells compared with the adjacent normal tissues.
CONCLUSION: The results suggested that the variations of the VLDLR subtype expression might be correlated with the progress and differentiation of gastroenteric carcinoma.
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Affiliation(s)
- Tao Chen
- Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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Abstract
Cajal-Retzius (CR) cells are an enigmatic class of neurons located at the surface of the cerebral cortex, playing a major role in cortical development. In this review, we discuss several distinct features of these neurons and the mechanisms by which they regulate cortical development. Many CR cells likely have extracortical origin and undergo cell death during development. Recent genetic studies report unique patterns of gene expression in CR cells, which may help to explain the developmental processes in which they participate. Moreover, a number of studies indicate that CR cells, and their secreted gene product, reelin, are involved in neuronal migration by acting on two key partners, migrating neurons and radial glial cells. Emerging data show that these neurons are a critical part of an early and complex network of neural activity in layer I, supporting the notion that CR cells modulate cortical maturation. Given these key and complex developmental properties, it is therefore conceivable for CR cells to be implicated in the pathogenesis of a variety of neurological disorders.
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Affiliation(s)
- Eduardo Soriano
- Institut de Recerca Biomedica de Barcelona, Parc Cientific de Barcelona, University of Barcelona, Barcelona 08028, Spain.
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Hiramatsu N, Chapman RW, Lindzey JK, Haynes MR, Sullivan CV. Molecular characterization and expression of vitellogenin receptor from white perch (Morone americana). Biol Reprod 2004; 70:1720-30. [PMID: 14766733 DOI: 10.1095/biolreprod.103.023655] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
A full-length (4021 base pair [bp]) cDNA encoding a polypeptide (844 amino acids) with a predicted mass of 93 kDa and other characteristic structural features of a vertebrate vitellogenin receptor (VgR) was isolated from a white perch (Morone americana) ovarian cDNA library. Northern blotting performed using a specific digoxygenin-labeled VgR cDNA probe revealed a distinct approximately 4.1 kilobase (kb) hybridization signal in an mRNA preparation obtained from previtellogenic perch ovaries. The deduced amino acid sequence of the perch VgR was 89% and 82% identical, respectively, to that of the tilapia and rainbow trout. Because it possessed an eight-repeat ligand-binding domain (LR8) but lacked an O-linked sugar domain (-), the perch VgR was identified as a non-O-linked form of VgR (LR8-). Unlike the case in other vertebrates investigated, including tilapia and trout, no species of mRNA encoding an O-linked form of VgR (LR8+) could be detected when perch ovarian or liver mRNA reverse transcripts or cDNA libraries were screened by PCR using primer sets flanking the putative O-linked sugar domain. These novel findings call into question the assumptions that an LR8+ splice variant of the VgR always is dominantly present in somatic tissues and exists at lower levels in ovarian tissues to sequester lipoproteins distinct from Vg. A SYBR-green-based real-time reverse transcription-polymerase chain reaction assay was developed and used to quantitatively measure VgR expression in gonadal and somatic tissues, for the first time in any vertebrate. The main site of perch VgR mRNA expression was the ovary and the highest level of VgR mRNA expression was in ovaries whose largest follicles contained previtellogenic oocytes. Expression of VgR mRNA decreased with oocyte growth during vitellogenesis and was very limited in ovulated eggs. These quantitative results verify the concept that growing oocytes must extensively recycle LR8- forms of the VgR.
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Affiliation(s)
- Naoshi Hiramatsu
- Department of Zoology, College of Agriculture and Life Sciences, North Carolina State University, Raleigh,North Carolina 27695-7617, USA
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Abstract
Architectural changes in the developing human brain are discussed based on the matrix cell theory. Neural stem cells/matrix cells with self-renewing ability and multipotency exist in the developing human brain in vivo. The brain development is divided into three stages and the cell differentiation is time regulated. Immunohistochemical distribution of various markers for brain development is summarized and categorized along with differentiation lineages. Particularly, the existence of glial fibrillary acidic protein is re-evaluated in the developing human brain. The commonly used terms and concepts "radial glial fiber" or "subventricular zone" are also re-evaluated.
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Affiliation(s)
- Yasuhiro Nakamura
- Department of Pathology, St. Mary's Hospital, Kurume 830-8543, Japan.
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